The advent of high-throughput genomics and associated technologies have afforded the ability to begin to ask detailed questions about the biology of whole systems and the interactions of those parts, rather than examining parts of the system in isolation. This application contains studies that explore the dynamic interactions between pathogens, hosts, their microbiota and the immune system with the goal to provide a more comprehensive understanding of the determinants of infectious disease outcomes. Pathogens subvert host cells by using their gene products to manipulate cellular pathways for survival and replication; in turn, host cells respond to the invading pathogen through changes in gene expression. Deciphering these complex temporal and spatial dynamics to identify novel virulence factors or host response pathways is essential for complete understanding of the infectious disease process. However, even these approaches don't fully take into account the complexity of the interactions, given that the normal microbiota are also key players in these interactions. The majority of the members of the normal microbiota exist as mutualists that live in association with the host without causing disease. Yet, the interactions of a host, its microbiota, and a pathogen in the context of the host immune response, co-infections, anti-microbial therapies, or vaccines can greatly affect disease outcome. The integration of the high-throughput technology with the biological question highlights the evolution of genomics as an area of research from a strictly observational tool of only a few years ago, to being an integral part in the examination of the disease process and human health as a whole. The genomic viewpoint is becoming more complete, as we can begin to simultaneously characterize the interactions of host, pathogen and microbiota. The current application takes a systematic approach to the examination of not just a single pathogen, or the ecosystem that the pathogen is part of, but examines the impact of the other microbes and host factors on the infectious disease process. The integration of the data from these complex interactions is providing the foundation for a deeper understanding of health and disease. This proposal includes a highly collaborative group of investigators centered within the Institute for Genome Sciences at the University of Maryland and New York University who are experts in their respective areas of pathogen biology, but also are pioneers in the field of genomics. We expect that these studies will address major gaps in knowledge related to the molecular pathogenesis of viral, bacterial, fungal and parasitic pathogens.